Project Summary Cachexia is a devastating state of malnutrition brought about by a synergistic combination of decreased appetite and increased metabolism of fat and lean body mass. While many chronic diseases such as cirrhosis, Alzheimer's disease, and congestive heart failure are associated with cachexia, it is particularly prevalent in pancreatic ductal adenocarcinoma (PDAC). There are currently no effective treatments for PDAC-associated cachexia, and its mechanisms are poorly understood. Our lab previously identified the actions of the inflammatory cytokines IL-1? and TNF? on hypothalamic neurons and their role in driving cachexia symptoms. Cytokines are produced in the hypothalamus during states of systemic inflammation, and injection of IL-1? and TNF? into the brain recapitulate the signs and symptoms of cancer cachexia. However, chronic central administration of these cytokines leads to rapid desensitization and loss of sickness response. Furthermore, the source of cytokines in the central nervous system (CNS) during cachexia is not known. Leukocytes produce cytokines during numerous chronic diseases, yet their role in cachexia is unknown. Circulating immune cells infiltrate the brain and are important mediators of sickness response in states of systemic stress such as inflammatory liver disease and bacterial infection. However, the role of infiltrating leukocytes in the brain during cancer cachexia has not been investigated. I found that, in a murine model of PDAC-associated cachexia, thousands of peripheral immune cells infiltrate the brain. The majority of these cells are neutrophils. Furthermore, the chemokine CCL2, which is important for myeloid cell recruitment to the brain during states of peripheral and central inflammation, is highly upregulated in the brain during PDAC. Lastly, a large percentage of neutrophils in the brain express CCR2 (the receptor for CCL2) and animals lacking CCR2 have a 43% decrease in neutrophils in the brain during PDAC. My hypothesis is that during PDAC, peripheral leukocytes are recruited to the brain by the chemokine CCL2 and are key drivers of chronic hypothalamic inflammation and subsequent cachexia. This project proposes to first assess for the presence of infiltrating immune cells in other organs affected in cachexia during PDAC. It will then determine if neutrophils are necessary for cachexia by depleting these cells during PDAC. It will also determine if immune cell infiltration into the brain is necessary for PDAC-associated cachexia by blocking leukocyte migration. Lastly, this project proposes to selectively inhibit CCL2 in the brain using genetic and pharmacologic techniques to determine if CCL2 is important for immune cell recruitment to the brain, maintaining chronic hypothalamic inflammation, and cachexia during PDAC. Taken together, achieving the goals of this project will: 1) Enhance our understanding of cachexia, 2) provide multiple novel therapeutic targets for cachexia, and 3) introduce a novel immune system - brain pathway by which peripheral leukocytes drive chronic neuroinflammation during malignant disease.